Tania Mudrikova

Drug–Drug Interactions Between Antiretroviral and Immunosuppressive Agents in HIV-Infected Patients After Solid Organ Transplantation: A Review

Since the introduction of combination antiretroviral therapy (cART) resulting in the prolonged survival of HIV-infected patients, HIV infection is no longer considered to be a contraindication for solid organ transplantation (SOT). The combined management of antiretroviral and immunosuppressive therapy proved to be extremely challenging, as witnessed by high rates of allograft rejection and drug toxicity, but the profound drug-drug interactions between immunosuppressants and cART, especially protease inhibitors (PIs) also play an important role. Caution and frequent drug level monitoring of calcineurin inhibitors, such as tacrolimus are necessary when PIs are (re)introduced or withdrawn in HIV-infected recipients. Furthermore, the pharmacokinetics of glucocorticoids and mTOR inhibitors are seriously affected by PIs. With the introduction of integrase inhibitors, CCR5-antagonists and fusion inhibitors which cause significantly less pharmacokinetic interactions, have minor overlapping toxicity, and offer the advantage of pharmacodynamic synergy, it is time to revaluate what may be considered the optimal antiretroviral regimen in SOT recipients. In this review we provide a brief overview of the recent success of SOT in the HIV population, and an update on the pharmacokinetic and pharmacodynamic interactions between currently available cART and immunosuppressants in HIV-infected patients, who underwent SOT.

A Randomized Controlled Study of Accelerated Versus Standard Hepatitis B Vaccination in HIV-Positive Patients

BACKGROUNDnIn human immunodeficiency virus (HIV)-infected patients, the immunogenicity of hepatitis B vaccines is impaired. The primary and secondary aims of our study were to investigate the effectiveness and compliance of 2 different vaccination regimen in an HIV-infected population.nnnMETHODSnA noninferiority trial with a 10% response margin was designed. Included were patients ≥ 18 years old, with negative HBsAg/anti-HBc serology, and not previously vaccinated against hepatitis B. Patients were stratified according to CD4(+) cell count: <200, 200-500, >500. Participants received 10 μg HBvaxPRO intramuscularly according to a 0-1-3 week schedule or the standard 0-4-24 week schedule. Anti-HBs levels were measured at week 28, considered protective ≥ 10 IU/L.nnnRESULTSnModified intention to treat analysis in 761 patients was performed. Overall response difference was 50%(standard arm) versus 38.7% (accelerated arm) =11.3% (95% confidence interval [CI], [4.3, 18.3]), close to the 10% response margin. In CD4(+) cell count group 200-500 cells/mm(3,) the response difference was 20.8% (95% CI [10.9, 30.7]). However, the response difference in CD4(+)cell count group >500 cells/mm(3) was -1.8% (95% CI [-13.4,+9.7]). Compliance was significantly superior with the accelerated schedule, 91.8% versus 82.7% (P ≤ .001).nnnCONCLUSIONnIn HIV-infected patients, compliance with an accelerated hepatitis B vaccination schedule is significantly better. The efficacy of an accelerated schedule proved to be non-inferior in CD4(+) cell count group >500 cells/mm(3).nnnCLINICAL TRIALS REGISTRATIONnCT00230061.

Presence of occult HBV but near absence of active HBV and HCV infections in people infected with HIV in rural South Africa.

Human immunodeficiency (HIV), hepatitis B (HBV), and hepatitis C (HCV) viruses are endemic in Sub‐Saharan Africa, but data regarding the prevalence of hepatitis co‐infections in HIV‐positive individuals residing there are limited. The aim of the study was to determine the prevalence of HBV, HCV, and occult HBV (presence of HBV‐DNA in the absence of HBsAg) in a rural, South African cohort. The results were compared to various ethnic groups in a Dutch cohort of people infected with HIV. Antiretroviral‐naïve individuals with HIV from both a rural South African clinic (nu2009=u2009258), and a Dutch University hospital (nu2009=u2009782), were included. Both serological (HBV and HCV) and molecular (occult HBV) assays were performed. Logistic regression analysis was used to define independent predictors of a hepatitis co‐infection. HBV and HCV prevalence rates in the South African cohort were exceptionally low (0.4%, 1/242 and 0.8%, 2/242, respectively), compared to those observed in Caucasians (HBV 4.4% and HCV 10.9%) and African immigrants (HBV 8.9% and HCV 4.8%). Conversely, occult HBV was observed in a considerable proportion (10%, 6/60) of South African patients who were anti‐HBc‐positive but HBsAg‐negative. Occult infections were less frequent in Caucasians and Africans in the Dutch cohort (3.2% and 1.4%, respectively). Independent predictors for occult HBV were not identified, but a trend towards more occult HBV at lower CD4 counts was observed. Local HBV/HCV prevalence data are needed to optimize vaccination and antiretroviral treatment strategies. Occult HBV in patients with HIV may be missed regularly when molecular analyses are not available. J. Med. Virol. 83:929–934, 2011.

Interferon-gamma release assays (IGRAs) in high-endemic settings: could they play a role in optimizing global TB diagnostics? Evaluating the possibilities of using IGRAs to diagnose active TB in a rural African setting

The number of patients suffering from tuberculosis (TB) globally is increasing. Due to the HIV epidemic, most patients suffering from TB reside in sub-Saharan Africa. In order to improve TB diagnostics, new tests - interferon-gamma release assays (IGRAs) - have been developed over the last decade. In this paper we evaluate the possible use of these tests in diagnosing or excluding active TB in high HIV-burden, resource-limited settings. The inability to differentiate between active and latent TB, limited data on IGRA performance in HIV-infected patients, observed false-negative results, high costs, and logistic problems limit the potential benefit of IGRAs. We also present two theoretical study designs in order to further assess IGRAs. Setting up a study on this subject is complicated by the frequent unavailability of mycobacterial cultures, the difficulty in acquiring prospective data, and the impossibility of denying treatment to a patient suspected of having active TB. We feel that current evidence does not support the implementing of IGRAs in clinical practice in settings with high endemic latent TB infection (LTBI) and high HIV prevalence. As these settings are the ones that suffer the most from the TB epidemic, we believe that the role of IGRAs in global TB control is questionable.

Residual viremia is preceding viral blips and persistent low-level viremia in treated HIV-1 patients.

Background It has been suggested that low-level viremia or blips in HIV-infected patients on antiretroviral treatment are related to assay variation and/or increased sensitivity of new commercial assays. The 50-copy cut-off for virologic failure is, therefore, under debate. Methods Treated patients with low-level viremia (persistent viral loads (VL) of 50–1000 copies/mL, group A, Nu200a=u200a16) or a blip (single detectable VL, group B, Nu200a=u200a77) were compared to a control group (consistently suppressed viremia since start therapy (<50 copies/mL), Nu200a=u200a79). Residual viremia (detectable viral RNA <50 copies/ml) in the year preceding the first VL above 50 copies/mL (T0) was determined using Roche Cobas-Amplicor v1.5 or CAP-CTM v2.0. Subsequent virologic failure (2 consecutive VLs>500 or 1 VL>1000 copies/mL that was not followed by a VL<50 copies/mL; median follow up 34 months) was assessed. Results Significantly more patients in groups A and B had residual viremia in the year preceding T0 compared to controls (50% and 19% vs 3% respectively; p<0.001). Residual viremia was associated with development of low-level viremia or blips (OR 10.9 (95% CI 2.9–40.6)). Subsequent virologic failure was seen more often in group A (3/16) and B (2/77) than in the control group (0/79). Conclusion Residual viremia is associated with development of blips and low-level viremia. Virologic failure occurred more often in patients with low-level viremia. These results suggest that low-level viremia results from viral production/replication rather than only assay variation.

Pretransplantation pharmacokinetic curves of tacrolimus in HIV-infected patients on ritonavir-containing cART: a pilot study.

Background Ritonavir is an extremely strong inhibitor of P450 cytochrome 3A, which is the main metabolizing enzyme of tacrolimus. Subsequently, the pharmacokinetics of tacrolimus are affected to a large extend by the coadministration of ritonavir in HIV-infected transplant recipients. Therefore, to prevent overexposure directly posttransplantation in HIV-infected patients on ritonavir-containing cART, the predictive value of a pretransplantation pharmacokinetic curve of tacrolimus was explored. Methods A pretransplantation pharmacokinetic model of tacrolimus in these patients was developed, and a posttransplantation dosing advice was established for each individual patient. The pharmacokinetic population parameters were compared with HIV-negative patients, and predictive value of the pretransplantation curves was assessed in patients after the transplantation procedure. Results No significant difference was found between the model-predicted and actual posttransplantation 24 h-tacrolimus levels (14.6 vs. 17.8 ng/mL, P=0.19). As the simulated pharmacokinetic curves lacked an absorption peak every 12 h, the mean 12 h-AUC was approximately 40 % lower compared with AUC’s reported in HIV-negative recipients, when similar trough levels were targeted. Conclusion In conclusion, pretransplantation curves of tacrolimus seem a promising tool to prevent overexposure directly posttransplantation in patients on ritonavir-containing cART and raising trough levels to achieve an exposure equivalent to HIV-negative recipients is suggested.

Pegylated interferon-alpha monotherapy leads to low response rates in HIV-infected patients with acute hepatitis C

BACKGROUNDnDespite a rising incidence of acute HCV in patients infected with HIV, the optimal therapeutic strategy (pegylated interferon-α [PEG-IFN-α] monotherapy or in combination with ribavirin) is still under debate.nnnMETHODSnA total of 23 HIV-infected patients were prospectively diagnosed with acute HCV and treated with PEG-IFN-α2a monotherapy (180 μg/week) for 24 or 48 weeks. Add-on ribavirin was allowed from week 4 of therapy onwards. There were three patients who were not included for different reasons. Blood samples were routinely drawn for viral load measurement and IL28B polymorphism analysis.nnnRESULTSnSpontaneous viral clearance occurred in 1 (4%) patient. Nineteen patients (13 genotype 1 and 6 genotype 4) received treatment with PEG-IFN-α monotherapy (3 with add-on ribavirin) resulting in a rapid virological response (HCV RNA<50 IU/ml at week 4) in 7 (37%) patients. A sustained virological response (SVR) was reached in 7 (37%) patients, whereas 9 (47%) patients were null-responders to treatment (that is, <2 log₁₀ drop in HCV RNA at week 12 of therapy). The unfavourable G allele of the IL28B polymorphism rs8099917 was detected in 66% of the non-responders. In case of re-emergence of HCV viraemia after treatment discontinuation, sequence analysis of quasispecies confirmed an HCV relapse in 3 patients while 2 patients were re-infected by their previously non-responding partner.nnnCONCLUSIONSnPEG-IFN-α monotherapy resulted in a low SVR rate and a high percentage of null-response, whereas non-SVR was associated with a polymorphism in the IL28B gene (rs8099917).

Evolution and viral characteristics of a long-term circulating resistant HIV-1 strain in a cluster of treatment-naive patients

BACKGROUNDnTransmitted resistant HIV may revert to wild-type in the absence of drug pressure due to reduced replication capacity (RC). We observed eight therapy-naive patients infected with HIV harbouring four mutations at nucleoside reverse transcriptase inhibitor (NRTI) resistance-related positions: M41L, T69S, L210E and T215S. If partial reverted resistance patterns like these are detected at baseline, concerns for more extensive resistance in the quasispecies often directs selection of first-line combination antiretroviral therapy (cART) towards more complex regimens.nnnMETHODSnGenotypic resistance testing and phylogenetic analysis was performed using pol sequences of 400 therapy-naive patients and 1322 patients with at least one NRTI-related mutation. Reverse transcriptase (RT) genes were cloned into a reference strain and RC was investigated.nnnRESULTSnPhylogenetic analysis showed that all eight patients are part of a transmission cluster (bootstrap value 92%). The patients resided in three distinct geographical regions and were either homosexually or heterosexually infected. Prior negative serology and analysis of base ambiguity demonstrated circulation for at least 7 years. In vivo evolution showed a mixture with wild-type (T215S/T) in only one untreated patient more than 6 years after diagnosis. The reverted resistance pattern did not confer a substantial reduction in RC compared with wild-type, explaining its persistence in vivo and long-term circulation in the population. Four patients started cART; three of them received quadruple cART. All patients showed good virological and immunological response.nnnCONCLUSIONSnLong-term circulation transcending distinct regions and transmission groups suggests reversion occurred in previous hosts in the transmission chain. Identification of clusters using epidemiological data and active-partner tracing may broaden therapeutic options in cases of transmitted resistance.

Infection with the frequently transmitted HIV-1 M41L variant has no influence on selection of tenofovir resistance

OBJECTIVESnIn ∼10% of newly diagnosed HIV-1 patients, drug-resistant viral variants are detected. In such transmitted HIV-1 variants, the thymidine analogue mutation (TAM) M41L is frequently observed as a single resistance mutation and these viral variants often belong to phylogenetic transmission clusters. The presence of at least three TAMs, in particular patterns with M41L/L210W, impairs the efficacy of the extensively used drug tenofovir. We investigated whether the presence of a single M41L mutation at baseline influences the selection of resistance to tenofovir and emtricitabine in vitro and in vivo.nnnMETHODSnThe impact of M41L on the development of drug resistance to tenofovir and emtricitabine was determined by extensive in vitro selection experiments and investigation of the virological outcome of patients on a first-line regimen.nnnRESULTSnThe presence of a single M41L mutation did not influence the selected mutational profile or the genetic barrier to resistance to tenofovir and/or emtricitabine during long-term in vitro selection experiments. In vivo, virological outcome of first-line regimens containing tenofovir and emtricitabine was comparable between patients diagnosed with HIV-1 harbouring M41L (n=17, 16 were part of one transmission cluster) and WT virus (n=248).nnnCONCLUSIONSnDetection of a single M41L reverse transcriptase mutation at baseline did not influence the development of resistance in vitro or virological outcome on tenofovir-containing regimens in patients belonging to a large transmission cluster. Our results indicate that a high genetic barrier regimen may not be required when patients are diagnosed with HIV variants containing a single M41L mutation in reverse transcriptase.

Efficacy of tenofovir and efavirenz in combination with lamivudine or emtricitabine in antiretroviral-naive patients in Europe

BACKGROUNDnThe combination of tenofovir and efavirenz with either lamivudine or emtricitabine (TELE) has proved to be highly effective in clinical trials for first-line treatment of HIV-1 infection. However, limited data are available on its efficacy in routine clinical practice.nnnMETHODSnA multicentre cohort study was performed in therapy-naive patients initiating ART with TELE before July 2009. Efficacy was studied using ITT (missing or switchu200a=u200afailure) and on-treatment (OT) analyses. Genotypic susceptibility scores (GSSs) were determined using the Stanford HIVdb algorithm.nnnRESULTSnEfficacy analysis of 1608 patients showed virological suppression to <50 copies/mL at 48 weeks in 91.5% (OT) and 70.6% (ITT). Almost a quarter of all patients (22.9%) had discontinued TELE at week 48, mainly due to CNS toxicity. Virological failure within 48 weeks was rarely observed (3.3%, nu200a=u200a53). In multilevel, multivariate analysis, infection with subtype B (Pu200a=u200a0.011), baseline CD4 count <200 cells/mm³ (Pu200a<u200a0.001), GSS <3 (Pu200a=u200a0.002) and use of lamivudine (Pu200a<u200a0.001) were associated with a higher risk of virological failure. After exclusion of patients using co-formulated compounds, virological failure was still more often observed with lamivudine. Following virological failure, three-quarters of patients switched to a PI-based regimen with GSS <3. After 1 year of second-line therapy, viral load was suppressed to <50 copies/mL in 73.5% (OT).nnnCONCLUSIONSnIn clinical practice, treatment failure on TELE regimens is relatively frequent due to toxicity. Virological failure is rare and more often observed with lamivudine than with emtricitabine. Following virological failure on TELE, PI-based second-line therapy was often successful despite GSS <3.